tbuckley/cabot-search huggingface dataset:
Clinical characteristics of gastrointestinal stromal tumors with lymph node metastasis: A retrospective single-centre case-controlled study.
Authors: Xinhua Zhang, Xiaodan Guo, Shaoqing Huang, Yanzhe Xia, Xuefu Zhou
Journal: Journal of Clinical Oncology (2023)

e23509 Background: Lymph node metastasis of gastrointestinal stromal tumors (GISTs) rarely occurs, and lymphadenectomy is not routinely performed in GIST resection. To date, the relevant characteristics and prognosis of GIST patients with lymph node metastasis are not well known. Methods: From January 2010 to December 2021, GIST patients who underwent lymph node resection were enrolled in this study from a GIST referral centre. All patients were divided into either the LN- group (GISTs without lymph node metastasis) or the LN+ group (GISTs with lymph node metastasis). The clinicopathological features and follow-up data were analysed, and propensity score matching (PSM) was conducted to reduce bias caused by confounders. Results: Out of 1024 surgical patients, 198 patients (age, 52.23±13.54 years; 56.6% males) underwent GIST resection with lymph node dissection for lymphadenopathy, and 17 patients had lymph node metastases (17/1024, 1.66%; 17/198, 8.59%). The LN+ group had a higher mitotic count (P = 0.012) and a higher proportion of distant metastasis (P &lt; 0.001) than the LN- group. After PSM, 28 patients were included (18 in the LN- group and 10 in the LN+ group). The LN- group had both longer postoperative progression-free survival (PFS, not reached vs. 15.0 months, P = 0.002) and overall survival (OS) than the LN+ group, but the difference in OS was not statistically significant (not reached vs. 35.0 months, P = 0.069). Conclusions: The rate of lymph node metastasis in GISTs is low. Lymph node metastasis may be a less common form of distant metastasis. Moreover, GIST with lymph node metastasis has an unfavourable prognosis. Further studies are warranted to identify GISTs with lymph node involvement and the potential involved mechanism. [Table: see text]
Circulating tumor DNA and association with CAR-T cell therapy response in gastric and pancreatic cancer patients.
Authors: Sindhu Kubendran, Julia L. Boland, Adham A Jurdi, Audrey Ween, Gabriel Baker, Hong Ma, Raffaele Baffa, Zonghai Li, Gregory P. Botta
Journal: Journal of Clinical Oncology (2023)

4053 Background: Circulating tumor DNA (ctDNA) is a form of cell free DNA that can be used to detect and measure cancer molecular residual disease (MRD) before and after systemic therapy. There are no data pertaining to the assessment of MRD in patients with solid tumors treated with chimeric antigen receptor T-cell (CAR-T) therapy. Here, we evaluated a tumor-informed ctDNA assay in the setting of gastric and pancreatic malignancies treated with claudin18.2 (CT041)-targeted CAR-T cell therapy (NCT04404595). Methods: A single-center review between 7/1/2021 – 1/1/2023 identified 10 patients with pancreatic or gastric carcinoma who received CAR-T CT041 cell therapy. Eight patients were ctDNA positive prior to treatment and had blood samples serially drawn before and after CAR-T cell therapy. Banked plasma was analyzed for ctDNA using a tumor-informed Signatera, mPCR-NGS ctDNA assay (Natera, Inc.). The correlative prognostic value of ctDNA to predict response after CAR-T cell therapy was analyzed by RECIST 1.1 criteria. Results: Pre- and post-treatment serial ctDNA was available for 8 of 10 (3/5 gastric and 5/5 pancreatic cancer) patients and all 8 were ctDNA positive prior to CAR-T CT041 cell therapy. The median nadir of ctDNA was on day 14 after CT041 infusion.Of the 8 patients with detectable ctDNA, 5 (62.5%) became undetectable at some time after CT041 therapy, while 3 (37.5%)remained ctDNA positive throughout treatment. The disease control rate (DCR) was 80% for anytime negative ctDNA patients (4/5). Of patients with responsive disease after CT041 CAR-T, 2/3 (67%) achieved undetectable ctDNA and 1/3 (33%) had a ctDNA reduction by 95%. Both patients with stable disease developed undetectable ctDNA. In those patients with progressive disease, 1/3 (33%) had a negative anytime ctDNA. One patient with a complete response had undetectable ctDNA and target lesion response, then later developed progressive disease detectable by ctDNA 3 months prior to radiography. Overall survival was higher (9.1 months vs. 3.7 months) in those who achieved anytime undetectable ctDNA. Conclusions: Tumor-informed ctDNA correlates with response to CAR-T cell therapy in gastrointestinal malignancies. Ongoing clinical trials of CT041 CAR-T cell therapy will continue ctDNA analysis prospectively. Characteristics of initially ctDNA positive patients receiving CAR-T therapy. Clinical trial information: NCT04404595 . [Table: see text]
Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias.
Authors: Prithviraj Bose, Nico Gagelmann, Vikas Gupta, Donal P. McLornan, Pankit Vachhani, Haifa Kathrin Al-Ali, Haris Ali, Philipp Treskes, Sarah Buckley, Karisse Roman-Torres, Bart L. Scott
Journal: Journal of Clinical Oncology (2023)

7068 Background: In patients with myelofibrosis (MF), JAK inhibitor therapy can improve both splenomegaly and disease symptoms. Unfortunately, dosing – and thus efficacy – of available current JAK1/2 inhibitors is frequently limited in patients with cytopenic MF due to drug-induced exacerbation of cytopenias. Pacritinib is a novel JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has been studied at full dose in patients with MF regardless of cytopenias. Here, we present data on spleen and symptom benefit in pacritinib-treated patients across the cytopenic spectrum, stratified by both baseline platelet (PLT) count and hemoglobin (HB) level. Methods: Evaluable patients treated with pacritinib in the PERSIST-1 and PERSIST-2 studies were analyzed, stratified by baseline PLT (&lt;100, ≥100x10 9 /L) and HB (&lt;8, 8 to &lt;10, ≥10 g/dL). Groups were analyzed for depth of spleen volume response (SVR), modified total symptom score (TSS) response, patient global impression of change (PGIC), and dose intensity. Results: Of 276 patients evaluable for spleen response, median age was 67 years, 51.5% had grade 3 fibrosis, 70% had primary MF, and 16% had prior JAK2 inhibitor exposure. Median dose intensity was &gt;99.7% for the duration of the study across PLT and HB subgroups. Overall, 80% of patients had ≥10% SVR (SVR-10), 75.5% had TSS-10, and 78% reported that their symptoms were improved at week 24. Week 24 spleen reduction occurred consistently across PLT and HB strata, with 84-93% and 86-90% of patients respectively (Table). SVR-35 occurred in 23-25% of patients across PLT strata and in 21-28% of patients across HB strata. Symptom response was also consistent across strata, though TSS-50 occurred at highest rates (62.5%) in patients with HB &lt;8 g/dL. There was no diminution in symptom burden reduction in patients with thrombocytopenia (Table). Across all subgroups, at least three-quarters of patients reported symptoms were “improved” at week 24. Conclusions: Pacritinib demonstrates consistent efficacy for spleen and symptom response in patients with MF regardless of blood counts. This consistent effect may be related to pacritinib’s unique kinome profile and its ability to be delivered at full dose in patients regardless of cytopenias. Clinical trial information: NCT01773187 , NCT02055781 . [Table: see text]
Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing granulocytopenia in sarcoma patients receiving doxorubicin combined with ifosfamide: A prospective, randomized, non-inferiority phase II study.
Authors: Li Fan, Ting Ye, Zhongliang Wang, Rubo Cao, Bicheng Wang, Ling Peng, Jing Chen
Journal: Journal of Clinical Oncology (2023)

e24173 Background: Prophylactic use of rhG-CSF is routinely recommended in patients with a high risk of febrile neutropenia (FN) after chemotherapy. Currently, rhG-CSF is mostly used in clinical practice. However, PEG-rhG-CSF tends to be a substitute due to its convenience and long-acting effect. Regarding concerns about its efficacy and safety, whether PEG-rhG-CSF could be prophylactically used after these regimens with a high risk of FN is still in doubt. Doxorubicin combined with ifosfamide is commonly applied in sarcoma patients and is one of the most serious myelosuppressive chemotherapy regimens in solid tumors. We compared the efficacy and safety of PEG-rhG-CSF with rhG-CSF in the prevention of severe granulocytopenia and FN, in patients receiving this representative regimen. Methods: This was a single-center, prospective, randomized, crossover, non-inferiority phase II trial. Patients with sarcoma suitable for doxorubicin combined with ifosfamide treatment were enrolled. All patients received 2 cycles of chemotherapy and were randomly assigned to either the AOB group (PEG-rhG-CSF used in 1st cycle and rhG-CSF in 2nd cycle) or BOA group (rhG-CSF used in 1st cycle and PEG-rhG-CSF in 2nd cycle). Blood monitoring every other day until ANC ≥ 2×10 9 /L in two consecutive tests. The primary endpoints were the frequency and duration of grade 4 granulocytopenia after prophylactic use of PEG-rhG-CSF and rhG-CSF respectively, the secondary endpoints were the frequency and duration of febrile neutropenia, and proportion of antibiotic use. Results: From Jan 1, 2018 to Aug 31, 2021, 70 patients were enrolled, 35 each in AOB and BOA. There were no statistical differences in the incidence and duration of grade 4 granulocytopenia (85.7% vs. 77.0%, p = 0.1; 1.34d vs. 1.41d, p = 0.70), the proportion and duration of febrile neutropenia (12.8% vs. 8.2%, p = 0.77; 0.6d vs. 0.8d, p = 0.74), and the proportion of antibiotics used (19.1% vs. 14.9%, p = 0.79) when comparing PEG-rhG-CSF vs. rhG-CSF in prophylactical use. The incidence of grade 4 granulocytopenia in both groups was comparable in 1st cycle (90.9% vs. 96.0%, p = 0.47), but in 2nd cycle it was significantly lower in AOB than that in BOA (54.5% vs. 88.0%, p = 0.01). The lowest value of ANC was higher in AOB in 2nd cycle (0.32G/L vs. 0.12G/L, p = 0.03). Conclusions: This study demonstrated PEG-rhG-CSF could prevent granulocytopenia and FN in sarcoma patients receiving doxorubicin combined with ifosfamide, with comparable efficacy and toxicities as rhG-CSF. Considering the convenience in use and patient compliance, PEG-rhG-CSF could be an effective and reasonable alternative to rhG-CSF. Clinical trial information: ChiCTR1900021945 .
Efficacy and safety of pembrolizumab versus sintilimab treatment in patients with advanced squamous lung cancer: A real-world study in China.
Authors: Wenyu Yang, Ming Gao, Ting Wang, Fangfang Jing, Fan Zhang, Haitao Tao, Junxun Ma, Yi Hu, Lijie Wang
Journal: Journal of Clinical Oncology (2023)

e21045 Background: Both pembrolizumab and sintilimab have been approved for the first-line treatment of patients with advanced squamous lung cancer in China. The differences of the two drugs in efficacy and safety are unclear. The aim of this study was to compare the efficacy and safety in advanced squamous lung cancer patients in real world. Methods: This was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The aim was to compare the objective response rate (ORR), disease control rate (DCR),progression-free survival (PFS), overall survival (OS) and adverse events (AEs). Results: A total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P = 0.634). The DCR was 92.10% and 92.10% in two groups respectively (P = 0.991). The median PFS was 22.2 months in sintilimab group compared with 16.5 months in pembrolizumab group[ HR = 0.743; 95% CI: 0.479-1.152; P = 0.599]. Patients treated with sintilimab had a median OS of 30.7 months and a median OS did not achieve with pembrolizumab. The incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63)in the sintilimab group, and 90.1% (91/101) in the pembrolizumab group. Conclusions: Sintilimab and pembrolizumab were similar as a first-line treatment for patients with advanced squamous lung cancer in efficacy and safety. [Table: see text]
An open-label window of opportunity trial to evaluate the activity of durvalumab and tremelimumab with platinum-based chemotherapy (gemcitabine and cisplatin) in intrahepatic cholangiocarcinoma.
Authors: Olumide B. Gbolahan, Mehmet Akce, Darryl Alan Outlaw, Grant Richard Williams, Sushanth Reddy, Jason Denbo, Richard D. Kim, Bassel F. El-Rayes, J. Bart Rose
Journal: Journal of Clinical Oncology (2023)

TPS4189 Background: Following surgical resection, the rate of recurrence of intrahepatic cholangiocarcinoma (ICC) is high. Expert groups recommend preoperative systemic therapy, particularly for resectable ICC with features that portend a high risk of recurrence. Based on data from ABC-02 the combination of gemcitabine and cisplatin (GC) is often used. This provides an objective response rate (ORR) of only 20% in ICC. The addition of durvalumab, an anti-PDL1 inhibitor to GC improves overall survival (OS) in the metastatic setting and is associated with an ORR of about 30%. On the other hand, while the addition of nab-Paclitaxel to GC provides an ORR of 34%, it was not associated with an improvement in OS in biliary tract cancer. It is therefore rationale to continue to explore and optimize immune checkpoint inhibitor development in ICC. We designed this study to determine the activity of durvalumab (D) and tremelimumab (T) (anti-CTLA4 ICPI) in combination with GC in resectable ICC with high-risk features. We plan to explore tumor intrinsic and tumor microenvironment related factors that will be associated with response (or lack thereof) to ICPI. Methods: This is a multicenter open-label, window of opportunity trial of the combination durvalumab and tremelimumab in combination with GC in resectable ICC with high-risk features. Inclusion criteria includes patients ≥18years with radiologically measurable and biopsy proven ICC that is surgically resectable but with high risk features (based on multidisciplinary tumor board discussion). Prespecified high-risk features include tumor size &gt;5cm, T1b-T4 lesion, multifocal tumors/tumor with satellite lesions, suspicious or involved lymph nodes (N1) and vascular involvement all thought to be technically resectable. Patients with extrahepatic metastasis will be excluded. D will be administered at 1500mg IV on Day 1 every 3 weeks for up to a maximum of 4 cycles. T, 300mg will be administered on Day 1 of cycle 1 only. G (1000mg/m2) and C (25mg/m2) will be administered by IV infusion on Days 1 and 8 every 3 weeks for a maximum of 4 cycles. The primary outcome measure is to demonstrate an ORR of 52%. Secondary objectives are to assess the feasibility and safety of the combination in ICC. Given the historical objective response rate of 25% and using one-sided exact test for single proportion, we will have 80% power to reject 25% ORR at α=0.05 when we observe ORR of 52% (Ho: Po=0.25 vs. Ha: Pa=0.52) from the study sample. The study is open at the O’Neal Comprehensive Cancer Center at the University of Alabama and will be open at other centers in the next few months. Clinical trial information: NCT04989218 .
Outcomes of individuals with clonal hematopoiesis evaluated at a cancer center.
Authors: Kelly Sharon Chien, Faustine Ong, Kunhwa Kim, Ziyi Li, Rashmi Kanagal-Shamanna, Courtney Denton Dinardo, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Koji Sasaki, Sherry Pierce, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2023)

7072 Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had other comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p = 0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin &lt; 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p = 0.0005) and hemoglobin &lt; 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p = 0.0005). Conclusions: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.
Genomics-based screening of novel therapeutic targets and biomarkers for lung cancer.
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2023)

e15093 Background: Since the number of lung cancer patients who show objective response to standard treatments is still limited, development of new anti-cancer agents with minimum risk of side effects and specific cancer biomarkers is urgently required. Methods: We have been screening new therapeutic targets and their companion biomarkers for lung cancer as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the candidate genes for their scarce expression in normal tissues, iii) To validate the clinicopathological importance of their protein expression by tissue microarray covering hundreds of lung cancers, and iv) To characterize their function for the growth and/or survival of lung cancer cells by siRNAs. Results: We identified dozens of candidate oncoproteins and selected a lung cancer cell division-associated protein 1 (LCDAP1). Immunohistochemical analysis showed that LCDAP1 was expressed in 171 of 267 (64%) non-small cell lung cancer (NSCLC) tissues but not in normal lung epithelia. LCDAP1 expression was significantly associated with poor prognosis for NSCLC patients. To investigate its function, we screened LCDAP1-binding protein in lung cancer cells and found an interaction of LCDAP1 with a member of 5'-to-3' DNA helicase that was also up-regulated in lung cancer cells. Knockdown of either of LCDAP1 or its binding partner expression with siRNAs significantly inhibited the growth of cancer cells. Conclusions: Our genomics-based screening could be useful to develop diagnostic and prognostic biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, and nucleic acid drugs against lung cancer.
Epigenetic profile of elevated cell free circulating nucleosomes in non-Hodgkin lymphoma.
Authors: Priscilla Van den Ackerveken, Alison Lobbens, Dorian Pamart, Guillaume Rommelaere, Marielle Herzog
Journal: Journal of Clinical Oncology (2023)

e15032 Background: Non-Hodgkin lymphoma (NHL) is a common type of hematological malignancy. The non-specific symptoms of lymphoma often delay diagnosis that is mainly based on a lymph node biopsy. However, due to their invasive nature, tissue biopsies have many limitations especially for monitoring therapeutic response where multiple biopsies may be required. Conversely, liquid biopsy offers a promising diagnosis and monitoring tool for cancer detection as it is noninvasive and easily repeatable over time compared to tissue biopsy. In this study, we investigated the circulating levels of intact nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) in NHL and healthy subjects. Then, as histone post-translational modifications (PTMs) of circulating nucleosomes are described as potential biomarkers of various solid cancers, we investigated the epigenetic profile of nucleosomes from NHL patients following nucleosome enrichment (Nu.Q Capture) combined with mass spectrometry (MS) compared to healthy donors. Methods: In plasma K2EDTA from 9 NHL and 5 healthy subjects, we measured levels of Nu.Q-H3.1 combined with the epigenetic profile of these circulating nucleosomes using our Nu.Q Capture- mass spectrometry protocol. Subsequently, the capability of the identified histone PTMs to differentiate between NHL and healthy plasma was tested in an independent cohort (n = 24 NHL patients and n = 35 healthy donors) and in two patients undergoing treatment course using available quantitative Nu.Q immunoassays. Results: We describe a high level of circulating H3.1-nucleosomes in human plasma NHL patients compared to healthy subjects. This level of H3.1-nucleosomes was correlated with an elevated concentration of cfDNA and is consistent with the DNA distribution size observed by the Bioanalyzer around 146 bp. In addition, the mass spectrometric analysis of the nucleosome enriched extracts allowed us to profile the epigenetic pattern of circulating nucleosomes in NHL patients. Our analysis demonstrated increased levels of H3.1 as well as the lysine acetylation and methylations of the histone H3 in plasma from NHL patients. Furthermore, the clinical validation of the histone PTMs pattern using immunoassays identified a significant increase in the levels of H3.1-nucleosomes as well as 6 histone PTMs (H3K9Me1, H3K27Me3, H3K36Me3, H3K9Ac, H3K14Ac, H3K18Ac) in NHL patients in comparison with healthy donors. Finally, the application of this histone PTMs pattern on NHL patients demonstrated the potential use of these new biomarkers present in liquid biopsy to evaluate the therapeutic response and monitoring of tumor progression. Conclusions: Our results indicate that levels of Nu.Q-H3.1 are particularly elevated in NHL patients and may be a useful diagnostic tool. Moreover, our work emphasizes the crucial roles of the epigenetic marks present on circulating nucleosomes to detect and monitor diseases such as lymphoma.